The present invention relates to antimicrobial polymers, and more specifically, to biodegradable cationic block copolymers prepared by ring opening polymerization and methods of their use for antimicrobial applications.
Due to the increasing resistance of bacteria to conventional antibiotics, peptide-based macromolecular antimicrobial agents have received significant attention. Most conventional antibiotics (e.g., ciprofloxacin, doxycycline and ceftazidime) do not physically damage the cell wall but penetrate into the target microorganism and act on specific targets. The antibiotic can, for example, cause breakage of double-stranded DNA by inhibition of DNA gyrase, block cell division, or trigger intrinsic autolysins. As a consequence, the bacterial morphology is preserved and the bacteria can easily develop resistance. In contrast, most cationic peptides (e.g., magainins, cecropins, protegrins and defensins) do not have a specific target in microbes. Instead, they interact with microbial membranes based on electrostatic interaction, thereby inducing damage to the microbial membranes which is hard to repair. It has been proven that the macromolecular cationic antimicrobial peptides can overcome bacterial resistance. The disintegration of cell membrane eventually leads to cell death. Although efforts have been made to design peptides with various structures over the last two decades, these materials have had limited success in clinical trials. To date, only four cationic peptides have successfully entered Phase III clinical trials for wound healing. This is mainly due to cytotoxicity caused by the cationic nature of peptides (e.g., hemolysis), short half-life in vivo (labile to proteases) and high manufacturing cost.
A number of cationic block copolymers that mimic the facially amphiphilic structure and antimicrobial functionalities of peptides have been proposed because they can be more easily prepared and the synthesis can be more readily scaled up when compared to peptides. For example, antimicrobial polynorbornene and polyacrylate derivatives, poly(arylamide), poly(beta-lactam), and pyridinium copolymers were synthesized. However, these antimicrobial polymers are non-biodegradable, which can limit their in vivo applications.
Consequently, a continuing need exists for biodegradable cationic block copolymers having low cytotoxicity and that form nano-size micelles having low CMC suitable for antimicrobial applications.